Our aim is to study genetic and environmental factors that control the formation of the connection between eye and brain. We are specifically interested in mechanisms that control whether or not retinal axons cross at the chiasm. This is important for at least two reasons: (1) to better understand the development of binocular vision in humans; and (2) to better understand genetic, molecular, and cellular factors that guide the growth of nerve fibers within the central nervous system. We use two complementary approaches to this important problem in visual system development. First, we will take advantage of powerful new genetic and experimental manipulations in mouse embryos: we will make experimental chimeras by combining albino embryos and transgenic embryos that carry human globin or human neurofilament genes. This will allow us to study the mechanism by which the albino mutation in the mouse sharply reduces the number of retinal ganglion cells with uncrossed projections into the optic tracts. Is the misrouting of retinal axons in pigment-deficient mutants due to an intrinsic defect of retinal ganglion cells, or is it secondary to the effects of the mutations on the environment through which retinal axons grow? Our second approach also focuses on the genetic control of axon guidance, but the approach is quite different. Here we plan to pursue genetic analysis of a highly unusual visual system mutation recently discovered in Belgian sheepdogs (Williams, Garraghty, and Goldowitz, 1991). In these mutants, the entire retinal projection is uncrossed. This striking genetic defect is opposite to that seen in albinos, in which an abnormally large number of optic axons cross at the chiasm. These achiasmatic mutants provide an excellent animal model of inherited nystagmus and should provide genuine insight into the molecular and genetic basis of normal and abnormal development of retinal connections. Three lines of research will be pursued to define the genetic basis of this inherited disease (1) cytogenetics, (2) breeding studies of the transmission of the disease, and (3) linkage analysis to map the location of the mutant gene. This work will provide a foundation for the isolation and characterization of the mutant gene and its product.